Work of the last project period identified a novel photoreceptor of the mammalian retina, a rare type of retinal ganglion cell (RGC) with axonal projections to the circadian pacemaker of the hypothalamus. These intrinsically photosensitive RGCs (ipRGCs) respond to light even when completely isolated from retinal synaptic networks. They contain a novel presumptive photopigment, melanopsin, and exhibit much lower sensitivity and more sluggish temporal properties than conventional photoreceptors. Their remarkably tonic light responses appear to faithfully encode ambient light levels. These cells thus form the basis of a specialized retinal output channel representing integrated retinal irradiance. This system supports a variety of 'non-image-forming' visual reflexes, including circadian entrainment, pupillary light reflex, seasonal adaptations in physiology, and acute photic modulation of plasma melatonin levels, sleep and activity. In the present project period, we will extend our understanding of the physiology of these novel photoreceptors through studies of their interactions with other retinal neurons and an examination of their phototransduction process. We will expand upon preliminary evidence for both excitatory and inhibitory influences of rod/cone networks on ipRGCs, exploring the basis and nature of these interactions and their implications for the behavior of these cells under natural conditions. In particular, we will trace these influences to specific bipolar and amacrine cell synaptic networks. We will test whether these influences alter the way in which ipRGCs encode stimulus intensity, or whether they confer either spatial or spectral antagonism upon their receptive fields. We will identify the major signaling components in the transduction cascade, from the photopigment, through various second messengers, to the light-activated ion channels. We will test directly the presumption that melanopsin is the photopigment. We will determine whether the transduction cascade resembles those in invertebrate photoreceptors, as suggested by invertebrate-like properties of the light response and presumptive photopigment. We will expand upon preliminary data implicating cyclic-nucleotide gated channels in the light-evoked conductance and will identify upstream signaling molecules coupling the photoactivated pigment to these or other light-activated channels. The findings will advance our understanding of the functional organization of a novel photosensory system in the mammalian retina with well-defined roles in homeostatic functions related to ambient illumination and the solar cycle.